Heteroarylamide pyrimidone compounds

ABSTRACT

The present invention discloses a series of pyrimidone derivatives represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: 
     
       
         
         
             
             
         
       
     
     Wherein X, Z, R1, R2, R3, R4, R5, R6, R7, n and m are as defined herein. Also disclosed herein are the methods of preparation of compounds of formula (I), intermediates therefor and their utility in treating a variety of disease conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International application No.PCT/IB2008/002,445, filed May 14, 2008, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofEuropean Patent Application No. 07290628.2, filed May 16, 2007.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies.

Interestingly, protein kinase B (AKT) phosphorylation of GSK3β resultsin a loss of its kinase activity, and it has been hypothesized that thisinhibition may mediate some of the effects of neurotrophic factors.Moreover, phosphorylation by GSK3β of β-catenin, a protein involved incell survival, results in its degradation by an ubiquitinilationdependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as p53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseasesand other pathologies where GSK3β is deregulated (Nature reviews Vol. 3,June 2004, p. 479-487; Trends in Pharmacological Sciences Vol. 25 No. 9,September 2004, p. 471-480; Journal of neurochemistry 2004, 89,1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384, 2002).

The neurodegenerative diseases include, in a non-limiting manner,Parkinson's disease, taupathies (e.g. Fronto temporal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy), Wilson's disease, Huntington's disease (The Journal ofbiological chemistry Vol. 277, No. 37, Issue of September 13, pp.33791-33798, 2002), Prion disease (Biochem. J. 372, p. 129-136, 2003)and other dementia including vascular dementia; acute stroke and othertraumatic injuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis (European Journal of Neuroscience, Vol. 22, pp. 301-309, 2005)peripheral neuropathies; retinopathies and glaucoma. Recent studies havealso shown that inhibition of GSK3β results in neuronal differentiationof embryonic stem cells (ESC) and support the renewal of human and mouseESCs and the maintenance of their pluripotency. This suggests thatinhibitors of GSK3β could have applications in regenerative medicine(Nature Medicine 10, p. 55-63, 2004).

Inhibitors of GSK3β may also find application in the treatment of othernervous system disorders, such as bipolar disorders (manic-depressiveillness). For example lithium has been used for more than 50 years as amood stabilizer and the primary treatment for bipolar disorder. Thetherapeutic actions of lithium are observed at doses (1-2 mM) where itis a direct inhibitor of GSK3β. Although the mechanism of action oflithium is unclear, inhibitors of GSK3β could be used to mimic the moodstabilizing effects of lithium. Alterations in Akt-GSK3β signaling havealso been implicated in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3β could be useful in treating cancers,such as colorectal, prostate, breast, non-small cell lung carcinoma,thyroid cancer, T or B-cell leukemia and several virus-induced tumors.For example, the active form of GSK3β has been shown to be elevated inthe tumors of colorectal cancer patients and inhibition of GSK3β incolorectal cancer cells activates p53-dependent apoptosis andantagonizes tumor growth. Inhibition of GSK3β also enhancesTRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also playsa role in the dynamics of the mitotic spindle and inhibitors of GSK3βprevent chromosome movement and lead to a stabilization of microtubulesand a prometaphase-like arrest that is similar to that observed with lowdoses of Taxol. Other possible applications for GSK3β inhibitors includetherapy for non-insulin dependent diabetes (such as diabetes type II),obesity and alopecia.

Inhibitors of human GSK3β may also inhibit pfGSK3, an ortholog of thisenzyme found in Plasmodium falciparum, as a consequence they could beused for the treatment of malaria (Biochimica et Biophysica Acta 1697,181-196, 2004).

Recently, both human genetics and animal studies have pointed out therole of Wnt/LPR5 pathway as a major regulator of bone mass accrual.Inhibition of GSK3β leads to the consequent activation of canonical Wntsignaling. Because deficient Wnt signaling has been implicated indisorders of reduced bone mass, GSK3β inhibitors may also be used fortreating disorders of reduced bone mass, bone-related pathologies,osteoporosis.

According to recent data, GSK3β inhibitors might be used in thetreatment or prevention of Pemphigus vulgaris.

Recent studies show that GSK3beta inhibitor treatment improvesneutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitorswill be useful for the treatment of neutropenia induced by cancerchemotherapy.

Previous studies have shown that GSK3 activity decreases LTP, anelectrophysiological correlate of memory consolidation, suggesting thatinhibitor of this enzyme may have procognitive activity. Procognitiveeffects of the compound could find application for the treatment ofmemory deficits characteristic of Alzheimer's disease, Parkinsondisease, age-associated memory impairment, mild cognitive impairment,brain trauma, schizophrenia and other conditions in which such deficitsare observed.

Inhibitors of GSK3β may also find application in the treatment ofparenchymal renal diseases (Nelson P J, Kidney International Advanceonline publication 19 Dec. 2007) and in the prevention or treatment ofmuscle atrophy (J. Biol. Chem. (283) 2008, 358-366)

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides as an object of the invention thepyrimidone derivatives represented by formula (I) or salts thereof,solvates thereof or hydrates thereof:

wherein:X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C₁₋₂alkyl group and a hydrogen atom;Z represents a bond, an oxygen atom, a nitrogen atom substituted by ahydrogen atom or a C₁₋₃ alkyl group, a sulfur atom, a methylene groupoptionally substituted by one or two groups chosen from a C₁₋₆ alkylgroup, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂ perhalogenatedalkyl group or an amino group;R1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, the ringbeing optionally substituted by a C₁₋₆ alkyl group, a C₁₋₆ alkoxy groupor a halogen atom;R2 represents a 4-15 membered heterocyclic group, this group beingoptionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkylgroup, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂perhalogenated alkoxy group, a C₁₋₆ halogenated alkoxy group, a nitro, acyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylaminogroup, a S—(C₁₋₆-alkyl) group, an heterocyclic group, an aryl group, anheteroaryl group, a O-aryl group or a S-aryl group, the above-mentionedgroups being optionally substituted by 1 to 4 substituents selected froma C₁₋₆ alkyl group, a halogen atom, a C₁₋₆alcoxy group, a C(O)O(C₁₋₆-alkyl) or a C(O)O (aryl) group, the aryl optionally substituted by1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, aC₁₋₆ alkoxy group;R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;R4 represents a hydrogen atom or a C₁₋₆ alkyl group;R5 represents a hydrogen atom, a C₁₋₆ alkyl group;R6 represents a hydrogen atom, a C₁₋₆ alkyl group;R7 represents a hydrogen atom or a C₁₋₆ alkyl group; andn represents 0 to 3 and m represents 1 in the form of a free base or ofan addition salt with an acid.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;malaria, bipolar disorders (manic depressive illness); schizophrenia;alopecia or cancers such as colorectal, prostate, breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia,several virus-induced tumors. The medicament could also find anapplication in regenerative medicine, Pemphigus vulgaris, neutropeniaand bone diseases.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the diseases are neurodegenerativediseases and are selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, taupathies (e.g. Fronto temporal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy), Wilson's disease, Huntington's disease, Prion disease and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis; peripheral neuropathies; retinopathies and glaucoma, and theaforementioned medicament in the form of pharmaceutical compositioncontaining the above substance as an active ingredient together with oneor more pharmaceutical additives.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the bones diseases are osteoporosis.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and the saltsthereof, and the solvates thereof and the hydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedor cyclo alkyl group having 1 to 6 carbon atoms, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexylgroup, isohexyl group, and the like.

The 4-15 membered heterocyclic group represents an unsaturated, fullysaturated or partially saturated mono- or polycyclic group (for example4 to 15 members) containing carbons atoms one to seven heteroatomschosen from N, O, and S. Examples of heterocyclic groups includepyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole,oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole,pyridine, pyrimidine, pyrazine, pyridazine, triazine, furofuran,thienothiophen, pyrrolopyrrole, furopyrrole, thienopyrrole,pyrroloimidazole, furoimidazole, thienoimidazole, pyrrolopyrazole,furopyrazole, thienopyrazole, pyrrolotriazole, furotriazole,thienotriazole, imidazoimidazole, furotetrazole, thienotetrazole,imidazopyrazole, pyrrolo-oxazole, pyrrolo-thiazole, imidazotriazole,imidazo-oxazole, imidazo-thiazole, triazolotriazole, pyrazolo-oxazole,pyrazolo-thiazole, pyrrolotetrazole, triazolo-oxazole,triazolo-thiazole, imidazotetrazole, furo-oxazole, furo-thiazole,pyrazolotetrazole, oxazolo-oxazole, oxazolo-thiazole, triazolotetrazoleoxazoloisoxazole oxazoloisothiazole, pyrrolo-isoxazole,pyrrolo-isothiazole, imidazo-isoxazole, imidazo-isothiazole,pyrazolo-isoxazole, pyrazolo-isothiazole, triazolo-isoxazole,triazolo-isothiazole, isoxazolo-isoxazole, isoxazolo-isothiazole,furo-isoxazole, furo-isothiazole, isoxazolo-oxadiazole,isoxazolo-thiadiazole, pyrrolo-oxadiazole, pyrrolothiadiazole,imidazo-oxadiazole, imidazo-thiadiazole, pyrazole-oxadiazole,pyrazolothiadiazole, triazolo-oxadiazole, triazolo-thiadiazole,furo-oxadiazole, furo-thiadiazole, isoxazolo-oxadiazole,isoxazolo-thiadiazole, oxazolo-oxadiazole, oxazolo-thiadiazole,isothiazolo-thiadiazole, indole, isoindole, benzimidazole, indazole,indolizine, benzofuran, isobenzofuran, benzothiophene, benzo[c]thiophen,pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine,tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine,pyrazolopyrimidine, triazolopyrimidine, tetrazolopyrimidine,pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine,tetrazolopyrazine, pyrrolopyridazine, imidazopyridazine,pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine,pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine,tetrazolotriazine, furopyridine, furopyrimidine, furopyrazine,furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine,oxazolopyrazine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine,isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine,isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine,oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine,benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine,thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine,thiazolopyridine, thiazolopyrimidine, thiazolopyrazine,thiazolopyridazine, thiazolotriazine, isothiazolopyridine,isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine,isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine,thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine,benzothiazole, benzoisothiazole, benzothiadiazole, quinoline,isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline,naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine,pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine,pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine,pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine,pyridazinotriazine, triazinotriazine, benzotriazole, benzodioxepine,benzodioxane, benzodioxine, diazepane. These heterocycles can exist alsoin a partially or fully saturated form, for example as an illustrationdihydrobenzofuran, tetrahydroquinoline etc. . . .

The heteroaryl group is an unsaturated 4-15 membered heterocyclic group;

The heterocyclic group is a saturated or partially saturated 4-15membered heterocyclic group;

The 6-10 membered heterocyclic group represents an unsaturated, fullysaturated or partially saturated mono- or polycyclic group (for example6 to 10 members) containing carbons atoms one to seven heteroatomschosen from N, O, and S. Examples of heterocyclic groups includepyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole,benzimidazole, indazole, indolizine, benzofuran, isobenzofuran,benzothiophene, benzo[c]thiophen, pyrrolopyridine imidazopyridine,pyrazolopyridine, triazolopyridine, tetrazolopyridine,pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine,triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine,imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine,pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine,triazolopyridazine, tetrazolopyridazine, pyrrolotriazine,imidazotriazine, pyrazolotriazine, triazolotriazine, tetrazolotriazine,furopyridine, furopyrimidine, furopyrazine, furopyridazine,furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine,oxazolopyridazine, oxazolotriazine, isoxazolopyridine,isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine,isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine,oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine,benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine,thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine,thiazolopyridine, thiazolopyrimidine, thiazolopyrazine,thiazolopyridazine, thiazolotriazine, isothiazolopyridine,isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine,isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine,thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine,benzothiazole, benzoisothiazole, benzothiadiazole, quinoline,isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline,naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine,pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine,pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine,pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine,pyridazinotriazine, triazinotriazine, benzotriazole, benzodioxepine,benzodioxane, benzodioxine, diazepane. These heterocycles can exist alsoin a partially or fully saturated form, for example as an illustrationdihydrobenzofuran, tetrahydroquinoline etc. . . .

The C₁₋₆ alkoxy group represents an alkyloxy group having 1 to 6 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl or alkoxy group represents an alkyl oralkoxy group wherein all the hydrogen atoms have been substituted by ahalogen, for example a CF₃ or C₂F₅; O—CF₃ or O—C₂F₅;

The C₁₋₆ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has been replaced by a halogen atom;

The C₁₋₆ halogenated alkoxy group represents an alkyl group wherein atleast one hydrogen has not been substituted by an halogen atom;

The C₁₋₆ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group, isopentylamino groupand the like;

The C₂₋₁₂ dialkylamino group represents an amino group substituted bytwo C₁₋₆ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group and the like;

The aryl group represents an aromatic mono or bicyclic ring (for example6 to 10 members) such as phenyl, naphthyl, pentalene, azulene,heptalene, indacene, acenaphthylene, benzocyclooctatetraene,bicyclo[4.2.0]octa-1,3,5,7-tetraene,bicyclo[5.1.0]octa-1,3,5,7-tetraene,bicyclo[6.2.0]deca-1,3,5,7,9-pentaene.

A leaving group L represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well known in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention.

The pyrimidone derivatives represented by the aforementioned formula (I)may have one or more asymmetric carbon atoms. As for the stereochemistryof such asymmetric carbon atoms, they may independently be in either (R)and (S) configuration, and the derivative may exist as stereoisomerssuch as optical isomers, or diastereoisomers. Any stereoisomers in pureform, any mixtures of stereoisomers, racemates and the like fall withinthe scope of the present invention.

An object of the present invention includes also compounds representedby formula (I) with m is 1 and defined by the different subsets (1) to(10) taken separately or mixed:

(1) R1 represents a 4- or 5-pyrimidine ring or a 4-pyridine ring; thering being optionally substituted by a C₁₋₂ alkyl group, a C₁₋₂ alkoxygroup or a halogen atom; and/or(2) R2 represents a 6-10 membered heterocyclic group, this group beingoptionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkylgroup, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂perhalogenated alkoxy group, a C₁₋₆ halogenated alkoxy group, a nitro, acyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylaminogroup, a S—(C₁₋₆-alkyl) group, an heterocyclic group, an aryl group, anheteroaryl group, a O-aryl group or a S-aryl group, the above-mentionedgroups being optionally substituted by 1 to 4 substituents selected froma C₁₋₆ alkyl group, a halogen atom, a C₁₋₆ alkoxy group, a C(O)O(C₁₋₆-alkyl) or a C(O)O (phenyl) group, the phenyl optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, ahalogen atom, a C₁₋₆ alkoxy group;(3) R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;and/or(4) R4 represents a hydrogen atom or a C₁₋₆ alkyl group; and/or(5) R5 represents a hydrogen atom, a C₁₋₆ alkyl group; and/or(6) R6 represents a hydrogen atom, a C₁₋₆ alkyl group; and/or(7) R7 represents a hydrogen atom or a C₁₋₆ alkyl group; and/or(8) X represents two hydrogen atoms, an oxygen atom or a C₁₋₂ alkylgroup and a hydrogen atom; and/or(9) Z represents a bond, an oxygen atom, a nitrogen atom substituted bya hydrogen atom or a C₁₋₃ alkyl group, a methylene group optionallysubstituted by one or two groups chosen from a C₁₋₃ alkyl group, ahydroxyl group, a C₁₋₃ alkoxy group, a C₁₋₂ perhalogenated alkyl groupor an amino group; and/or(10) n represents 0 to 3, in the form of a free base or of an additionsalt with an acid.

Another object of the present invention includes compounds representedby formula (I) with m being 1 defined by the different subsets (1) to(10) taken separately or mixed:

-   -   (1) R1 represents an unsubstituted 4-pyrimidine ring; and/or    -   (2) R2 represents a benzodioxine ring, a pyrimidine ring,        naphthyridine ring, pyridine ring, dihydrobenzodioxine ring,        benzothiophene ring, the rings being optionally partially or        fully saturated and or being optionally substituted by 1 to 4        substituents selected from hydroxyl group, a C₁₋₆ alkyl group, a        S—(C₁₋₆ alkyl) group, a halogen atom, an amino, a C₁₋₂        perhalogenated alkyl group, C₁₋₆ alkoxy group, a C₁₋₂        perhalogenated alkoxy group; and/or    -   (3) R3 represents a hydrogen atom; and/or    -   (4) R4 represents a methyl; and/or    -   (5) R5 represents a hydrogen atom; and/or    -   (6) R6 represents a hydrogen atom; and/or    -   (7) R7 represents a hydrogen atom; and/or    -   (8) X represents an oxygen atom; and/or    -   (9) Z represents a bond; and/or    -   (10) n represents 0, in the form of a free base or of an        addition salt with an acid.

Examples of compounds of the present invention are shown in table 1,hereinafter. However, the scope of the present invention is not limitedby these compounds. The nomenclature is given according to IUPAC rules.

A further object of the present invention includes the group ofcompounds of table 1 of formula as defined hereunder:

-   1. [1,5]Naphthyridine-2-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide-   2. 6-Chloro-pyridine-2-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide-   3.    2-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-nicotinamide-   4. 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide-   5. Benzo[b]thiophene-2-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide-   6. 8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide-   7. 5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)ethyl]-amide-   8. 3-Methoxy-pyridine-2-carboxylic acid    [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide

As a further object, the present invention concerns also methods forpreparing the pyrimidone compounds represented by the aforementionedformula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Pyrimidone compounds represented by the aforementioned formula (I), maybe prepared according to the method described in the scheme 1.

(In the above scheme the definitions of R1, R2, R3, R4, R5, R6, R7, m,n, X and Z are the same as those already described for compound offormula (I)).

Following this method, the pyrimidone derivative represented by theabove formula (III), wherein R1, R3, R4, R5, R6 and m are as defined forcompound of formula (I), is allowed to react with a base such astriethylamine, sodium carbonate or potassium carbonate in a solvent suchas tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylacetamide,dimethylformamide or chloroform at a suitable temperature ranging from 0to 130° C. under ordinary air, then with a compound of formula (II),wherein R2, X, Z and n are as defined for compound of formula (I) and Lrepresents a leaving group preferably chlorine, bromide, to obtain thecompound of the aforementioned formula (I).

Alternatively compounds of formula (I) wherein X represents two hydrogenatoms may be prepared by reductive amination of a compound of formula(II) wherein X represents an oxygen atom and L represents a hydrogenatom, by a compound of formula (III) wherein R1, R3, R4, R5, R6 and mare as defined for compound of formula (I) and R7 is a hydrogen,according to well known methods to one skilled in the art.

Compound of formula (II) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

Compound of formula (III) may be prepared according to the methoddefined in scheme 2.

(In the above scheme the definitions of R1, R3, R4, R5, R6, and m arethe same as already described.)

According to this method, the 3-ketoester of formula (IV), wherein R1and R3 are as defined for compound of formula (I), R is an alkyl groupsuch as for example methyl or ethyl, is allowed to react with a compoundof formula (V) wherein R5, R6, and m are as defined for compound offormula (I) and Pg is a suitable protecting group such as for example aphthalimido group or an alkoxy carbonyl group. The reaction may becarried out in the presence of a base such as potassium carbonate orsodium hydroxide, in an alcoholic solvent such as methanol, ethanol andthe like or without, at a suitable temperature ranging from 25° to 140°C. under ordinary air, to obtain the compound of the aforementionedformula (VI). Compound of formula (VI) may be alkylated with a compoundof formula R4L, wherein R4 is as defined for compound of formula (I), Lrepresents a leaving group preferably chlorine or bromide, in presenceof a base such as potassium carbonate or sodium hydride, in a solventsuch as dioxane or dimethylformamide, to obtain, after removal of theprotecting group (Pg), compound of formula (III).

Additionally compound of formula (III) wherein R3 represents a hydrogenatom may be halogenated in order to give compounds of formula (III)wherein R3 is a halogen atom such as a bromine atom or a chlorine atom.The reaction may be carried out in an acidic medium such as acetic acidor propionic acid, in presence of bromosuccinimide or chlorosuccinimide,or bromine.

In addition, compounds of formula (IV) wherein R3 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, No. 45, pp 6113-6116, 1989.

In addition, compounds of formula (IV) wherein R3 represents a hydrogenatom may be obtained by analogy to the method described in patent DE2705582.

As a further object, the present invention concerns also the compoundsof formula (III) as intermediates of compounds of formula (I).

Compound of formula (IV) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

For example compounds of formula (IV), wherein R1 represents a pyridinering or a pyrimidine ring, optionally substituted by a C₁₋₆ alkyl group,C₁₋₆ alkoxy group or a halogen atom, can be prepared by reactingrespectively an isonicotinic acid or a pyrimidine-carboxylic acid,optionally substituted by a C₁₋₆ alkyl group, C₁₋₆ alkoxy group or ahalogen, with the corresponding malonic acid monoester. The reaction canbe carried out using methods well known to one skilled in the art, suchas for example in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

Compound of formula (V) may be synthesized according to well-knownmethods of one skilled in the art.

For example compound of formula (V), wherein m, R5 and R6 are as definedfor compound of formula (I) and a suitable protecting group Pg such asfor example a phthalimido group or alkoxy carbonyl group, may beprepared according to the method defined in scheme 3, starting fromcompound of formula (VII). The conditions which may be used are given inthe chemical examples.

Compound of formula (VII) is commercially available or may besynthesized according to well-known methods of one skilled in the art.

Compound of formula (VIII) may be synthesized according to the methodsdescribed in Bulletin of the Chemical Society of Japan (1979), 52(10),2938-41.

Compound of formula (V) may be synthesized according to the methodsdescribed in WO96/14844 and Journal of Organic Chemistry (1981), 46(12),455-65.

In the above reactions protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 3rd Ed. (John Wiley & Sons,Inc., New York) 1999.

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, taupathies (e.g.Fronto temporal dementia, corticobasal degeneration, Pick's disease,progressive supranuclear palsy), Wilson's disease, Huntington's disease,Prion disease and other dementia including vascular dementia; acutestroke and others traumatic injuries; cerebrovascular accidents (e.g.age related macular degeneration); brain and spinal cord trauma;amyotrophic lateral sclerosis, peripheral neuropathies; retinopathiesand glaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; malaria, manic depressiveillness; schizophrenia; alopecia; cancers such as colorectal, prostatebreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia, several virus-induced tumors and in bone relatedpathologies. The medicament could also find an application inregenerative medicine.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention; however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES Example 1 Compound No. 4 of Table 16-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid[2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide1.1 [2-(6-Oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)ethyl]-carbamic acidbenzyl ester

To a suspension of 6 g (23.3 mmol) of (2-Carbamimidoyl-ethyl)-carbamicacid benzyl ester hydrochloride (1:1) in 60 ml of ethanol were added0.93 g (23.3 mmol) of sodium hydroxide and 4.5 g (23.3 mmol) of ethyl3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the methoddescribed in patent DE2705582). The resulting mixture was stirred underreflux for 12 h. The cooled solution was evaporated to remove solvent.The resulting mixture was treated with water and the precipitate wasfiltered, washed with diethyl ether to afford 2.7 g (33%) of the desiredcompound as a brown powder.

Mp.: 252-254° C.

¹H NMR (DMSO-d⁶; 200 MHz)

δ (ppm): 9.30 (s, 1H); 9.00 (d, 1H); 8.25 (d, 1H); 7.40 (t, 1H); 7.30(m, 5H); 7.15 (s, 1H); 5.00 (s, 2H); 3.50 (m, 2H); 3.30 (brs, 1H); 2.80(m, 2H).

1.2[2-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-carbamicacid benzyl ester

To a suspension of 0.15 g (0.43 mmol) of[2-(6-Oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yl)-ethyl]-carbamic acidbenzyl ester in 5 mL of anhydrous dimethylformamide was added 0.06 g(0.47 mmol) of potassium carbonate. The resulting mixture was allowed tostir at room temperature for 15 minutes, cooled at 0° C. and 30 μl (0.43mmol) of methyl iodide were added dropwise.

The mixture was warmed at room temperature and stirred for 3 h. Waterwas added and the mixture extracted with diethyl acetate. The extractswere washed with a saturated aqueous solution of ammonium chloride,dried and evaporated. The residue was purified on preparative thin layerchromatography eluting with a mixture ofdichloromethane/methanol/aqueous ammonia solution (29%) in theproportions 95/5/0.5 to afford 0.1 g (64%) of the desired compound as abrown powder.

Mp.: 121-123° C.

¹H NMR (DMSO-d⁶; 200 MHz)

δ (ppm): 9.40 (s, 1H); 9.10 (d, 1H); 8.40 (d, 1H); 7.70-7.35 (m, 6H);7.25 (s, 1H); 5.10 (s, 2H); 3.70 (m, 2H); 3.60 (s, 3H); 3.20 (m, 2H).

1.3 2-(2-Amino-ethyl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one

1.43 g (3.93 mmol) of[2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-carbamicacid benzyl ester was dissolved in 4.43 g (31.44 mmol) of hydrobromideacid in acetic acid. The mixture was stirred at room temperature for 2 hand concentrated in vacuo. The resulting precipitate was dissolved inwater, basified with an aqueous solution of sodium hydroxide (30%) andextracted with a mixture of dichloromethane/methanol/aqueous ammoniasolution (29%) in the proportions 80/20/2. The combined extracts weredried over anhydrous sodium sulfate and concentrated in vacuo to give0.693 g of a white powder.

Mp.: 190-192° C.

¹H NMR (DMSO-d⁶; 200 MHz)

δ (ppm): 9.40 (s, 1H); 9.10 (d, 1H); 8.30 (d, 1H); 7.30 (s, 1H); 3.60(s, 3H); 3.20-2.90 (m, 4H); 1.90-1.50 (brs, 2H).

1.4 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid[2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide

To a solution of 0.1 g (0.43 mmol) of2-(2-Amino-ethyl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 4 mL ofdimethylformamide was added 0.086 g (0.43 mmol) of6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid and 80 μL (0.52 mmol) ofdiethyl phosphorocyanidate (DEPC). The resulting mixture was cooled at0° C., 60 μL (0.43 mmol) of triethylamine was added and stirred at roomtemperature for 1 h.

Water and diethylacetate were added and the resulting solution wasbasified with an aqueous solution of sodium hydroxide (30%). After 1 hat room temperature, the resulting precipitate was collected byfiltration and washed with water and diethyl ether to afford 0.110 g(62%) of the desired compound as a white powder.

Mp.: 207-209° C.

¹H NMR (DMSO-d⁶; 200 MHz)

δ (ppm): 9.35 (s, 1H); 9.10 (d, 1H); 8.50 (brt, 1H); 8.30 (d, 1H); 7.40(m, 1H); 7.30 (d, 1H); 7.10 (m, 1H); 5.10 (s, 2H); 4.90 (s, 2H); 3.90(m, 2H); 3.55 (s, 3H); 3.20 (m, 2H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 1.

The compounds have been prepared according to the methods of theexamples. In the table 1 Ph represents a phenyl group, m is 1, (Rot.)indicates the levorotatory or dextrorotatory properties of theenantiomeric compound.

TABLE 1 No. Rot R2 Z R1 R4 R5 R6 R7 X R3 n Mp ° C. salt 1

bond

CH₃ H H H O H 0 266-268 Free base 2

bond

CH₃ H H H O H 0 258-259 Free base 3

bond

CH₃ H H H O H 0 201-203 Free base 4

bond

CH₃ H H H O H 0 207-209 Free base 5

bond

CH₃ H H H O H 0 204-207 Free base 6

bond

CH₃ H H H O H 0 285 (Dec.) Free base 7

bond

CH₃ H H H O H 0 214-216 Free base 8

bond

CH₃ H H H O H 0 167-169 Free base

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm ³³P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta. Inhibitors were solubilized in DMSO (final solventconcentration in the reaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH. (Woodgett, J. R. (1989)Analytical Biochemistry 180, 237-241.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 are between 1 nanomolar to 3 micromolarconcentrations.

Formulation Example (1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100mg Lactose 200 mg Magnesium stearate 4 mg

(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg

(3) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A compound of the formula (I) or a salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C₁₋₂ alkyl group and a hydrogen atom; Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C₁₋₃ alkyl group, a sulfur atom, a methylene group optionally substituted by one or two groups chosen from a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂ perhalogenated alkyl group or an amino group; R1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, the ring being optionally substituted by a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group or a halogen atom; R2 represents a 4-15 membered heterocyclic group, this group being optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆ halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂ perhalogenated alkoxy group, a C₁₋₆ halogenated alkoxy group, a nitro, a cyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylamino group, a S—(C₁₋₆-alkyl) group, an heterocyclic group, an aryl group, an heteroaryl group, a O-aryl group or a 5-aryl group, the above-mentioned groups being optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a (C₁₋₆) alkoxy group, a C(O)O(C₁₋₆-alkyl) or a C(O)O (aryl) group, the aryl optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₆ alkoxy group; R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom; R4 represents a hydrogen atom or a C₁₋₆ alkyl group; R5 represents a hydrogen atom, a C₁₋₆ alkyl group; R6 represents a hydrogen atom, a C₁₋₆ alkyl group; R7 represents a hydrogen atom or a C₁₋₆ alkyl group; and n represents 0 to 3 and m represents
 1. 2. The compound according to claim 1, wherein R1 represents an unsubstituted 4-pyrimidine ring.
 3. The compound according to claim 1, wherein: R1 represents a 4- or 5-pyrimidine ring or 4-pyridine ring; the ring being optionally substituted by a C₁₋₂ alkyl group, a C₁₋₂ alkoxy group or a halogen atom; R2 represents a 6-10 membered heterocyclic group, this group being optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₆ halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂ perhalogenated alkoxy group, a C₁₋₆ halogenated alkoxy group, a nitro, a cyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylamino group, a S—(C₁₋₆-alkyl) group, an heterocyclic group, an aryl group, an heteroaryl group, a O-aryl group or a S-aryl group, the above-mentioned groups being optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a (C₁₋₆) alkoxy group, a C(O)O (C₁₋₆-alkyl) or a C(O)O (phenyl) group, the phenyl optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a (C₁₋₆) alkoxy group; R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom; R4 represents a hydrogen atom or a C₁₋₆ alkyl group; R5 represents a hydrogen atom, a C₁₋₆ alkyl group; R6 represents a hydrogen atom, a C₁₋₆ alkyl group; R7 represents a hydrogen atom or a C₁₋₆ alkyl group; X represents two hydrogen atoms, an oxygen atom or a C₁₋₂ alkyl group and a hydrogen atom; Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C₁₋₃ alkyl group, a methylene group optionally substituted by one or two groups chosen from a C₁₋₃ alkyl group, a hydroxyl group, a C₁₋₃ alkoxy group, a C₁₋₂ perhalogenated alkyl group or an amino group; and n represents 0 to 3; or a salt thereof.
 4. The compound according to claim 1, wherein: R1 represents an unsubstituted 4-pyrimidine ring; R2 represents a benzodioxine ring, a pyrimidine ring, naphthyridine ring, pyridine ring, dihydrobenzodioxine ring, benzothiophene ring, the rings being optionally partially or fully saturated and or being optionally substituted by 1 to 4 substituents selected from hydroxyl group, a C₁₋₆ alkyl group, a S—(C₁₋₆alkyl) group, a halogen atom, an amino, a C₁₋₂ perhalogenated alkyl group, C₁₋₆ alkoxy group, a C₁₋₂ perhalogenated alkoxy group; R3 represents a hydrogen atom; R4 represents a methyl; R5 represents a hydrogen atom; R6 represents a hydrogen atom; R7 represents a hydrogen atom; X represents an oxygen atom; Z represents a bond; and n represents 0; or a salt thereof.
 5. The compound according to claim 1 which is selected from the group consisting of: [1,5]Naphthyridine-2-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; 6-Chloro-pyridine-2-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; 2-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-nicotinamide; 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; Benzo[b]thiophene-2-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; 8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; 5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; and 3-Methoxy-pyridine-2-carboxylic acid [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide; or a salt thereof
 6. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and at least one pharmaceutically acceptable excipient.
 7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2 and at least one pharmaceutically acceptable excipient.
 8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3 and at least one pharmaceutically acceptable excipient.
 9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 and at least one pharmaceutically acceptable excipient.
 10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5 and at least one pharmaceutically acceptable excipient.
 11. A method of treating a disease in a patient, said disease selected from the group consisting of Alzheimer's disease, Parkinson's disease and taupathies, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 12. A method of treating a disease in a patient, said disease selected from the group consisting of non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 13. A method of treating a disease in a patient, said disease selected from the group consisting of breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus-induced tumors, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 14. A method of treating malaria in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 15. A method of treating a bone disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 16. A method of treating pemphigus vulgaris in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 17. A method for the treatment of neutropenia induced by cancer chemotherapy in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 18. A method for the treatment of a disease caused by cognitive and memory deficits in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 19. A method of inhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β), which comprises administering to a patient in need of said inhibition a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim
 1. 20. A compound of the formula (III):

wherein: R1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, the ring being optionally substituted by a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group or a halogen atom; R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom; R4 represents a hydrogen atom or a C₁₋₆ alkyl group; R5 represents a hydrogen atom, a C₁₋₆ alkyl group; R6 represents a hydrogen atom, a C₁₋₆ alkyl group; and m represents
 1. 21. A process for the preparation of a compound of formula (I) according to claim 1 comprising: reacting a compound of formula (III):

with a compound of formula (II):

wherein X, Z, R1, R2, R3, R4, R5, R6, m and n are as defined in claim
 1. 